These investigations were designed to further define the role of thiols in protection of cells against oxidative damage. As splenocytes, fibroblasts or epithelial cells divide, their capacity to cleave extracellular disulfides to free thiols increases proportionally. Additionally, splenocytes develop disulfide cleaving capacity in proportion to their antibody forming activity. Both antibody formation and cell proliferation are decreased by oxidative reagents only after the extracellular thiol concentration has been diminished by oxidation. Electrophoretic analysis of the extracellular thiols showed the presence not only of those present as disulfides in the initial culture medium but also cysteinyl glycine, a unique product of the amino acid transport enzyme Gamma-glutamyl transpeptidase (GammaGTP). Cell-associated GammaGTP activity also increases in proportion to cell proliferation. Specific irreversible inhibition of GammaGTP decreases not only GammaGTP activity, but also disulfide cleavage and cell proliferation. The cysteinyl glycine is the most rapidly oxidized of the thiols, implicating it as the primal thiol antioxidant. This defines GammaGTP as a simultaneous amino acid transport and antioxidant enzyme. Further studies defining the relevance of disulfide cleavage and GammaGTP activity in chronic inflammation are in progress.